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Copper(II)-Mediated Intermolecular C(sp2)−H Amination of Benzamides with Electron-Rich Anilines
No full textDespite significant progress, copper-catalyzed/
mediated C−H amination reactions with electron-rich anilines
remain an unsolved problem due to catalyst deactivation and
deleterious side reactions. Herein, we report a copper(II)-
mediated C(sp2)−H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory
drugs
Development of functionalised nanomaterials for delivery of multiple biomolecules into the cell
No full textThe overall goal of this thesis is to design and synthesis of functionalized nanoparticles and their therapeutic application. The synthesis of functionalized nanoparticles has been fully characterized by various spectroscopic and microscopic techniques. These functionalized nanoparticles have been used for delivery of multiple biomolecules simultaneously into the cell. Moreover, kinesin mediated intracellular cargo transport has been reconstituted with these functionalized nanoparticles as well as it has been used as a delivery vehicle for enhancement of the anticancer efficacy of the antimitotic peptides as well as the microtubule targeted short DNA. At the end of this thesis, it has also been shown that cyclodextrin, which is commonly used as a delivery vehicle interacts with tubulin/microtubules and delivers tubulin targeted drugs into the tubulin surface and preferentially into the cancer cell
MicroRNA profiling of cisplatinresistant oral squamous cell carcinoma cell lines enriched withcancer-stem-cell-like and epithelial-mesenchymal transition-type features
Get PDFOral cancer is of major public health problem in India. Current investigation was aimed to identify
the specific deregulated miRNAs which are responsible for development of resistance phenotype
through regulating their resistance related target gene expression in oral squamous cell carcinoma
(OSCC). Cisplatin-resistant OSCC cell lines were developed from their parental human OSCC cell lines
and subsequently characterised. The resistant cells exhibited enhanced proliferative, clonogenic
capacity with significant up-regulation of P-glycoprotein (ABCB1), c-Myc, survivin, β-catenin and a
putative cancer-stem-like signature with increased expression of CD44, whereas the loss of E-cadherin
signifies induced EMT phenotype. A comparative analysis of miRNA expression profiling in parental
and cisplatin-resistant OSCC cell lines for a selected sets (deregulated miRNAs in head and neck cancer)
revealed resistance specific signature. Moreover, we observed similar expression pattern for these
resistance specific signature miRNAs in neoadjuvant chemotherapy treated and recurrent tumours
compared to those with newly diagnosed primary tumours in patients with OSCC. All these results
revealed that these miRNAs play an important role in the development of cisplatin-resistance mainly
through modulating cancer stem-cell-like and EMT-type properties in OSCC
Exploring the Potential of 99mTc(CO)3-Labeled Triazolyl Peptides for Tumor Diagnosis
No full textIn recent years the authors have reported on 99mTc(CO)3-labeled peptides that serve as carriers for biomolecules
or radiopharmaceuticals to the tumors. In continuation of that work they report the synthesis of a pentapeptide
(Met-Phe-Phe-Gly-His; pep-1), a hexapeptide (Met-Phe-Phe-Asp-Gly-His; pep-2), and a tetrapeptide (Asp-Gly-
Arg-His; pep-3) and the attachment of 3-amino-1,2,4-triazole to the b carboxylic function of the aspartic acid
unit of pep-2 and pep-3. The pharmacophores were radiolabeled in high yields with [99mTc(CO)3(H2O)3]+ metal
aqua ion, characterized for their stability in serum and saline, as well as in His solution, and found to be
substantially stable. B16F10 cell line binding studies showed favorable uptake and internalization. In vivo
behavior of the radiolabeled triazolyl peptides was assessed in mice bearing induced tumor. The 99mTc(CO)3-
triazolyl pep-3 demonstrated rapid urinary clearance and comparatively better tumor uptake. Imaging studies
showed visualization of the tumor using 99mTc(CO)3-triazolyl pep-3, but due to high abdominal background,
low delineation occurred. Based on the results further experiments will be carried out for targeting tumor with
triazolyl peptide
Capturing state-dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights
No full textThe γ-amino butyric acid type A receptors (GABAA-Rs) are the key players in the mammalian brain that meditate fast
inhibitory neurotransmission events. The structural integrity of these ligand-gated ion channel controls chloride ion permeability, which in turn monitors important pharmacological functions. Despite ample studies on GABAA-Rs, there was a need for a study on full-length receptor structures, devoted to track structure–function correlations based on their dynamic behavior consideration. We have employed molecular dynamics simulations accompanied by other biophysical methods to shed light on sequential and unaddressed questions like How GABAA-R structure facilitates the entry of GABA molecules at its two orthosteric binding sites? After entry, what structural features and changes monitor site-wise GABA binding differences? In the same context, what are the roles and responsibilities of loops such as C and F? On physiologically relevant time scales, how open to close state transition occurs? How salt bridges such as E155-R207 and E153-R207 maintain statedependent C-loop structures? In an attempt, our simulation study unravels the complete course of GABA binding-unbinding pathway. This provides us with the relevant understanding of state-dependent dynamic events of GABAA-Rs
Substrate-Dependent Mechanistic Divergence in Decarboxylative Heck Reaction at Room Temperature
No full textWe report herein a Pd(II)-catalyzed Heck-type coupling between arene carboxylic acids and alkenes at room
temperature. Mechanistically, the reaction proceeds in two distinct pathways where electron-rich substrates undergo a palladium(II)-catalyzed decarboxylation and electron-deficient substrates proceed through silver(I)-assisted decarboxylation. Dimethyl sulfoxide (DMSO) or sulfide ligands have positive and negative roles in the
reaction outcome, respectively. The present protocol is combined for the peptide modification under mild reaction conditions
E. coli metabolic protein aldehydealcohol dehydrogenase-E binds to the ribosome: a unique moonlighting action revealed
Get PDFIt is becoming increasingly evident that a high degree of regulation is involved in the protein synthesis machinery entailing more interacting regulatory factors. A multitude of proteins have been identified recently which show regulatory function upon binding to the ribosome. Here, we identify tight association of a metabolic protein aldehyde-alcohol dehydrogenase E (AdhE) with the E. coli 70S
ribosome isolated from cell extract under low salt wash conditions. Cryo-EM reconstruction of the ribosome sample allows us to localize its position on the head of the small subunit, near the mRNA entrance. Our study demonstrates substantial RNA unwinding activity of AdhE which can account for the ability of ribosome to translate through downstream of at least certain mRNA helices. Thus far, in
E. coli, no ribosome-associated factor has been identified that shows downstream mRNA helicase activity. Additionally, the cryo-EM map reveals interaction of another extracellular protein, outer membrane protein C (OmpC), with the ribosome at the peripheral solvent side of the 50S subunit. Our result also provides important insight into plausible functional role of OmpC upon ribosome binding.
Visualization of the ribosome purified directly from the cell lysate unveils for the first time interactions
of additional regulatory proteins with the ribosom
Binding of the alkaloid aristololactam-β-Dglucoside and daunomycin to human hemoglobin:spectroscopy and calorimetry studies
No full textThe interaction of the plant alkaloid aristololactam-β-D-glucoside (ADG) and the anticancer agent daunomycin (DAN)
with human hemoglobin was studied by different spectroscopic and calorimetric methods. The binding affinity values of ADG and DAN, estimated from spectroscopic experiments, were 3.79 × 104 and 6.68 × 104 M−1, respectively. From circular dichroism, 3D fluorescence, and FTIR studies it was observed that, DAN induced stronger conformational changes than ADG in the protein. From synchronous fluorescence spectroscopy results, a pronounced shift in the maximum emission wavelength of tyrosine residues was observed in both cases suggesting that the drugs changed the polarity around tyrosine residues with marginal change around the tryptophan residues. The thermodynamics of the binding
interaction analyzed using microcalorimetry presented single binding events that were exothermic in nature in both cases.The binding was driven by large positive standard molar entropy changes with small favorable enthalpy contributions.Negative heat capacity changes in both cases are correlated to the involvement of significant hydrophobic forces in the complexation process. The affinity of DAN to Hb was higher than that of ADG
Management of Inflammation by Natural Polyphenols: A Comprehensive Mechanistic Update
No full textInflammation generates a systemic response against injury or infection from bacteria, viruses, and other pathogens. The welfare of host is the primary target of this process.
However, uncontrolled or inadequate regulation of the inflammatory response produces detrimental effects leading to the generation of various chronic disorders including atherosclerosis, type-2 diabetes, neurodegenerative disease, cancer and Alzheimer’s disease with severe
tissue damage. The exact identity of the inflammatory stimuli is still elusive as they function in multiple pathways; therefore targeting a particular pathway does not resolve the problem. Existing therapeutics targeting the inflammatory responses include steroidal antiinflammatory drugs (SAIDs) and nonsteroidal antiinflammatory drugs (NSAIDs). In spite of their numerous beneficial effects, both SAIDs as well as NSAIDs have their independent, unavoidable side effects, which discourage their prolonged therapeutic applications. Since the management of uncontrolled inflammation is critical for the general wellbeing, therefore an alternative source of multi-targeted non-toxic therapeutic intervention is mandatory. Plant-derived phenols constitute such a group of molecules that can be utilised to manage inflammation. They synergistically modulate several important components involved in multiple signalling pathways that regulate uncontrolled inflammation to exhibit their beneficial health effects. This review discusses the recent advances in
structure-function activity of some antiinflammatory polyphenols, their bioavailability enhancement, clinical/
preclinical findings with a view to provide knowledge for developing novel antiinflammatory drugs by following system biology of proinflammatory responses with minimal side effect
Urinary Exosomal microRNA-451-5p Is a Potential Early Biomarker of Diabetic Nephropathy in Rats
Get PDFNon-invasive renal signatures can help in serial monitoring of diabetic patients. We tested whether urinary exosomal (UE) microRNA (miR) analysis could non-invasively predict renal pathology in diabetic rats during the course of diabetes. Diabetes mellitus (DM) was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). Non-diabetic control (CTRL) rats were injected with vehicle. Insulin (INS) treatment (5U/d, s.c.) was provided to 50% of the DM rats. Urine samples were collected at weeks 3, 6, and 9 following injections and UE prepared. An increase in miR-451-5p and miR-16, observed by pilot small RNA sequencing of UE RNA, was confirmed by quantitative real-time polymerase chain reaction (qPCR) and selected for further study. Subsets of rats were euthanized after 3, 6, and 9 weeks of diabetes for renal pathology analysis, including
determination of the tubulointerstitial fibrotic index (TFI) and glomerulosclerotic index (GI) scores. qPCR showed a substantial rise in miR-451-5p in UE from DM rats during thecourse of diabetes, with a significant rise (median fold change >1000) between 3 and 6 weeks. Moreover, UE miR-451-5p at 6 weeks predicted urine albumin at 9 weeks (r = 0.76).
A delayed but significant rise was also observed for miR-16. In contrast, mean urine albumin only increased 21% between 3 and 6 weeks (non-significant rise), and renal TFI and GI were unchanged till 9 weeks. Renal expression of miR-451-5p and miR-16 (at 10 weeks) did not correlate with urine levels, and moreover, was negatively associated with indices of renal pathology (r�-0.70, p = 0.005 for TFI and r�-0.6, p�0.02 for GI). Overall, a relative elevation in renal miR-451-5p and miR-16 in diabetes appeared protective against diabetes- induced kidney fibrosis; while UE miR-451-5p may hold prognostic value as an earlyand sensitive non-invasive indicator of renal diseas